High affinity transport of L-glutamate into astrocyte is necessary for the termination of its excitatory signal and the prevention of its excitotoxic effects. The removal of glutamate from the synaptic cleft is carried out by both the sodum-dependent system and a newly identified chloride-dependent system. Preliminary studies indicate a substantial proportion of the glutamate binding lost in Alzheimer's Disease (AD) represent a decrease in this chloride-dependant glutamate transport system. The consequence of such a decrease may be an increased exposure to excessive levels of of extracellular glutamate and an increased risk of excitotoxic damage. Furthermore, as transport into astrocytes is an important step in the recycling of released glutamate, decreased uptake would also compromise important metabolic pathways. In contrast to the decrease observed in AD, chloride-dependant binding increases in the dentate gyrus of rats with entorhinal lesions. The increased binding reaches a maximum at a days and returns to normal after two weeks. This increased ability to transport glutamate may be a compensation response to protect the remaining neurons from the excitotoxic conditions that accompany neuronal degeneration. The inability to observe such a response in AD may indicate a greater susceptibility to excitotoxic damage and reflect and as yet uncharacterized deficit in this disorder. I propose to investigate the chloride-dependent uptake of glutamate and carry out detailed evalutions of i) its biochemical properties, ii) its mechanisms of induction, and iii) its alteration in AD. A detailed biochemical characterization of this system will identify substrates and inhibitors of this system and permit precise quantitation losses AD. On a physiological level, the transport studies will determine the contribution of the chloride- dependent uptake to the total removal of glutamate and allow assessments to be made of the consequences of their apparent loss in AD. The elucidation of the mechanisms involved in the induction of this transport system tray may identify a new deficit in astrocytes in AD and provide insight into the protective capacity of the CNS.